ABSTRACT This application for renewal continues an enduring interest in neural mechanisms by which gastrointestinal (GI) satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) by vagal afferents and are integrated with other controls of food intake. Glutamate is the principal neurotransmitter released by vagal afferent terminals in the nucleus tractus solitarius (NTS). As such, glutamate receptors in the NTS are pivotal to the transmission and processing of satiation signals. Our published results, demonstrating that hindbrain injections of N-methyl-D-aspartate-type glutamate receptor (NMDAR) antagonists increase meal size and prevent reduction of food intake by cholecystokinin (CCK) support this assertion. Although vagal afferent activation by GI stimuli reduce meal size, central neuropeptides and circulating hormones also control food intake by controlling meal size, suggesting that they may modulate or imitate the effects of GI stimuli. We postulate that brain peptides interact with NMDAR to control meal size by modulating the strength of glutamatergic vagal afferent synapses in the NTS. Our preliminary results suggest that interaction of vagal afferent NMDAR and melanocortin 4 receptors (MC4R) triggers long-lasting changes in vagal afferent synapsin phosphorylation that are consistent with strengthened vagal afferent synaptic function. Experiments of Aim 1 utilize pharmacological, immunochemical, chemogenetic and electrophysiological approaches to determine the nature of NMDAR participation in MC4R effects on vagal afferent synaptic function and control of meal size. Vagal afferents express type 1 and type 2 NPY receptors (Y1R and Y2R) as well as MC4R and NMDAR. We find that NTS injection of NPY or the Y2R agonist, PYY 3-36, increases food intake, an effect that is attenuated by NTS co-injection of SP-cAMP. In Aim 2 of the application we test the hypothesis that vagal afferent Y2R control food intake by antagonizing MC4R effects on PKA activation, synapsin phosphorylation and vagal afferent synaptic strength. Our long- term goal is to determine how NMDAR participate in modulation of vagal afferent synaptic strength to reduce food intake. A detailed appreciation of the mechanisms by which peptides and hormone interact with NMDAR to control of food intake is of significance to human health because it may provide avenues for therapeutic intervention in eating disorders and obesity.